Pulmonary hypertension (PH) has been previously classified as primary (idiopathic) or secondary. Recently, the World Health Organization (WHO) has classified pulmonary hypertension into five groups:
Group 1: pulmonary arterial hypertension (PAH);
Group 2: PH with left heart disease;
Group 3: PH with lung disease and/or hypoxemia;
Group 4: PH due to chronic thrombotic and/or embolic disease; and
Group 5: miscellaneous conditions (e.g., sarcoidosis, histiocytosis X, lymphangiomatosis and compression of pulmonary vessels).
See, for example, Rubin (2004) Chest 126:7-10.
Pulmonary arterial hypertension (PAH) is a particular type of PH and is a serious, progressive and life-threatening disease of the pulmonary vasculature, characterized by profound vasoconstriction and an abnormal proliferation of smooth muscle cells in the walls of the pulmonary arteries. Severe constriction of the blood vessels in the lungs leads to very high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from extreme shortness of breath as the heart struggles to pump against these high pressures. Patients with PAH typically develop significant increases in pulmonary vascular resistance (PVR) and sustained elevations in pulmonary artery pressure (PAP), which ultimately lead to right ventricular failure and death. Patients diagnosed with PAH have a poor prognosis and equally compromised quality of life, with a mean life expectancy of 2 to 5 years from the time of diagnosis if untreated.
Endothelin-1 (ET-1) is the primary member of a family of potent vasoconstrictor peptides, which are known to play an essential role in mammalian cardiovascular physiology. ET-1 is synthesized de novo and released from endothelial cells in response to a variety of factors, including angiotensin II, catecholamines, cytokines, hypoxia and shear stress. Two receptor subtypes, endothelin receptor type A (ETA) and endothelin receptor type B (ETB), mediate the effects of ET-1. In humans, the ETA receptor is preferentially expressed in vascular smooth muscle cells and is primarily responsible for the vasoconstrictive effects of ET-1. In contrast, ETB receptors are found mainly in the vascular endothelium, and their activation results in vasodilatation via production of nitric oxide and prostacyclin. The ETB receptor is also involved in regulation of circulating concentrations of ET-1, through effects on endothelin converting enzyme (ECE-1) expression, and the synthesis and reuptake of ET-1 by endothelial cells.
Ambrisentan is a non-sulfonamide, propanoic acid-class endothelin receptor antagonist (ERA) with high affinity (˜12 pM) for the ETA receptor. Ambrisentan is approved for sale by the U.S. Food and Drug Administration (FDA) for once-daily treatment of PAH and is marketed under the trade name Letairis®. Other selective type-A receptor antagonists include sitaxentan, atrasentan, and BQ-123.
Additional drugs such as phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are also approved for use in treating PAH. PDE5 inhibitors are drugs used to block the degradative action of phosphodiesterase type 5 on cyclic GMP in the arterial wall smooth muscle within the lungs and in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis.
Tadalafil is a PDE5 inhibitor, currently marketed under the name Adcirca® for the treatment of pulmonary arterial hypertension. The approved dose for pulmonary arterial hypertension is 40 mg (two 20-mg tablets) once daily. Adverse effects of tadalafil include hypotension, vision loss, hearing loss and priapism. Thus, methods of increasing the anti-PH efficacy of selective type-A ERA and PDE5 inhibitors, as well as reducing the potential adverse effects, are highly desirable. Other PDE5 inhibitors on the market or during development include avanafil, lodenafil, mirodenafil, sildenafil citrate, vardenafil and udenafil.
U.S. Patent Publication No. 2008/0139593 describes a method for treating pulmonary hypertension, comprising administration of a therapeutically effective amount of ambrisentan to a patient, wherein, at baseline, time from the first diagnosis of the condition in the subject is not greater than about two years. Also described is ambrisentan in combination with one or more suitable drugs selected from prostanoids, PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil, ERAs, calcium channel blockers, arylalkylamines, dihydropyridine derivatives, piperazine derivatives and other suitable compounds for use in combination therapy.
It has now been discovered that the combination of a selective type-A ERA and a PDE5 inhibitor has beneficial co-action resulting in potent relaxation of pulmonary contractions. For example, the co-action of ambrisentan and tadalafil provides enhanced efficacy in reducing endothelin-induced contraction of rat pulmonary arteries and aortas.